The serine/threonine kinase Akt is likely to play a role in tumorigenesis, as it has been found to be amplified and overexpressed in multiple human carcinoma cell lines and primary tumors. Furthermore, Akt has been shown to promote survival of cultured fibroblasts as well as primary cultures of cerebellar neurons. To date, the only known substrate for Akt is glycogen synthase kinase-3 (GSK3). However, a role of GSK3 in transformation of epithelial cells and in protection from programmed cell death has not been observed. Therefore, Akt is likely to utilize additional downstream effectors distinct from GSK3. The goal of this proposal is to characterize the effector-mediated pathways used by the Akt kinase to promote cell survival and to induce malignant transformation.
Two specific aims are proposed to accomplish this goal. We will first identify proteins which function as upstream regulators or downstream effectors of the Akt kinase. Second, we will assess the functional contributions of such effectors and regulators to Akt-mediated transformation as well as protection from apoptosis. Results from these studies will serve to elucidate the signaling pathways regulated by Akt, and, moreover, may aid in the development of new drug therapies to combat diseases such as cancer and neuro- degenerative disorders characterized by deregulated apoptosis.
